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CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma.

ABSTRACT: Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumors. HDACs are central players in the DNA damage signaling. We further confirmed that CYLD regulates radiation-induced DNA damage and repair response through inhibiting class I HDACs. Furthermore, CYLD mediates nasopharyngeal carcinoma cell radiosensitivity through class I HDACs. Thus, we identified the function of the CYLD-HDAC axis in radiotherapy and blocking HDACs by Chidamide can increase the sensitivity of cancer cells and tumors to radiation therapy both in vitro and in vivo. In addition, ChIP and luciferase reporter assays revealed that CYLD could be transcriptionally regulated by zinc finger protein 202 (ZNF202). Our findings offer novel insight into the function of CYLD in tumor and uncover important roles for CYLD-HDAC axis in radiosensitivity, which provide new molecular target and therapeutic strategy for tumor radiotherapy.

SUBMITTER: Li Y

PROVIDER: S-EPMC10824711 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma.

Li Yueshuo Y Yang Chenxing C Xie Longlong L Shi Feng F Tang Min M Luo Xiangjian X Liu Na N Hu Xudong X Zhu Yongwei Y Bode Ann M AM Gao Qiang Q Zhou Jian J Fan Jia J Li Xuejun X Cao Ya Y

Cell death & disease 20240129 1

Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumo ...[more]

PMID: 38287022

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Project description:BackgroundNew efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types. We therefore investigated the effects of combined Romidepsin and JQ1 treatment on UC and benign urothelial control cells.ResultsJQ1 alone induced cell cycle arrest, but only limited apoptosis in eight UC cell lines with strongly varying IC50 values between 0.18 and 10 μM. Comparable effects were achieved by siRNA-mediated knockdown of BRD4. Romidepsin and JQ1 acted in a synergistic manner across all UC cell lines, efficiently inhibiting cell cycle progression, suppressing clonogenic growth, and inducing caspase-dependent apoptosis. Benign control cells were growth-arrested without apoptosis induction, but retained long-term proliferation capacity. In UC cells, anti-apoptotic and oncogenic factors Survivin, BCL-2, BCL-XL, c-MYC, EZH2 and SKP2 were consistently downregulated by the drug combination and AKT phosphorylation was diminished. Around the transcriptional start sites of these genes, the drug combination enhanced H3K27 acetylation, but decreased H3K4 trimethylation. The cell cycle inhibitor CDKN1C/p57KIP2 was dramatically induced at mRNA and protein levels. However, Cas9-mediated CDKN1C/p57KIP2 knockout did not rescue UC cells from apoptosis.ConclusionOur results demonstrate significant synergistic effects on induction of apoptosis in UC cells by the combination treatment with JQ1 and Romidepsin, but only minor effects in benign cells. Thus, this study established a promising new small-molecule combination therapy approach for UC.

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CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma.

Publications

CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma.

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